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Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces Flavoviridis ATCC21892

Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces Flavoviridis ATCC21892

Jeffrey D Rudolf, Lance Bigelow, Changsoo Chang, Marianne E Cuff, Jeremy R Lohman, Chin-Yuan Chang, Ming Ma, Dong Yang, Shonda Clancy, Gyorgy Babnigg, Andrzej Joachimiak, George N Phillips Jr, Ben Shen

Biochemistry. 2015 Nov 17;54(45):6842-51.

PMID: 26512730

Abstract:

The bleomycins (BLMs), tallysomycins (TLMs), phleomycin, and zorbamycin (ZBM) are members of the BLM family of glycopeptide-derived antitumor antibiotics. The BLM-producing Streptomyces verticillus ATCC15003 and the TLM-producing Streptoalloteichus hindustanus E465-94 ATCC31158 both possess at least two self-resistance elements, an N-acetyltransferase and a binding protein. The N-acetyltransferase provides resistance by disrupting the metal-binding domain of the antibiotic that is required for activity, while the binding protein confers resistance by sequestering the metal-bound antibiotic and preventing drug activation via molecular oxygen. We recently established that the ZBM producer, Streptomyces flavoviridis ATCC21892, lacks the N-acetyltransferase resistance gene and that the ZBM-binding protein, ZbmA, is sufficient to confer resistance in the producing strain. To investigate the resistance mechanism attributed to ZbmA, we determined the crystal structures of apo and Cu(II)-ZBM-bound ZbmA at high resolutions of 1.90 and 1.65 Å, respectively. A comparison and contrast with other structurally characterized members of the BLM-binding protein family revealed key differences in the protein-ligand binding environment that fine-tunes the ability of ZbmA to sequester metal-bound ZBM and supports drug sequestration as the primary resistance mechanism in the producing organisms of the BLM family of antitumor antibiotics.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP11006330	Phleomycin from Streptomyces verticillus		11006-33-0	Price

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